RU2012117719A - Induction of Pluripotent Cells - Google Patents

Induction of Pluripotent Cells Download PDF

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RU2012117719A
RU2012117719A RU2012117719/10A RU2012117719A RU2012117719A RU 2012117719 A RU2012117719 A RU 2012117719A RU 2012117719/10 A RU2012117719/10 A RU 2012117719/10A RU 2012117719 A RU2012117719 A RU 2012117719A RU 2012117719 A RU2012117719 A RU 2012117719A
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substituted
non
substituent
inhibitor
substituents
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RU2012117719/10A
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Туньсянь ЛИНЬ
Шэн ДИН
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Зе Скрипс Ресеч Инститьют
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Priority to PCT/US2010/052896 priority patent/WO2011047300A1/en
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    • C12N2506/09Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from epidermal cells, from skin cells, from oral mucosa cells
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    • C12N2506/00Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells
    • C12N2506/13Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from connective tissue cells, from mesenchymal cells
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    • C12N2506/00Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells
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    • C12N2510/00Genetically modified cells

Abstract

1. A composition comprising an activin receptor-like kinase 5 (ALK5) inhibitor; a MAP / ERK kinase inhibitor (MEK); Rho kinase inhibitor (ROCK) .2. The composition of claim 1, further comprising a glycogen synthase 3 kinase inhibitor (GSK3). The composition of claim 1, further comprising a histone deacetylase inhibitor (HDAC). The composition of claim 1, wherein the ALK5 inhibitor is A-83-01 or SB431542.5. The composition according to claim 1, characterized in that the MEK inhibitor is PD0325901.6. The composition according to claim 1, characterized in that the ROCK inhibitor has the structure: where L is substituent or non-substituent C-Calkylene; y is an integer from 0 to 3; z is an integer from 0 to 5; X is -N =, -CH = or -CR =; R is hydrogen, substituted or unsubstituted alkyl, substituted or not substituted heteroalkyl, substituted or not substituted cycloalkyl, substituted or not substituted ate heterocycloalkyl substituted or non-substituted aryl, or substituted or non-substituted heteroaryl; R, R and R independently are —CN, —S (O) R, —NRR, —C (O) R, —NR-C (O) R, —NR — C (O) —OR, —C (O) NRR, —NRS (O) R, —OR, —S (O) NR, substituted or unsubstituted alkyl, substituted or non-substituted heteroalkyl, substituted or non-substituted cycloalkyl, substituted or non-substituted heterocycloalkyl, substituted or not amestiteli aryl, or containing substituents or substituents containing heteroaryl g

Claims (20)

1. A composition comprising
activin receptor kinase 5 inhibitor (ALK5);
MAP / ERK kinase inhibitor (MEK); and
Rho kinase inhibitor (ROCK).
2. The composition of claim 1, further comprising a glycogen synthase 3 kinase inhibitor (GSK3).
3. The composition of claim 1, further comprising a histone deacetylase inhibitor (HDAC).
4. The composition according to claim 1, characterized in that the ALK5 inhibitor are A-83-01 or SB431542.
5. The composition according to claim 1, characterized in that the MEK inhibitor is PD0325901.
6. The composition according to claim 1, characterized in that the ROCK inhibitor has the structure:
Figure 00000001
Where
L 2 represents substituent or non-substituent C 1 -C 10 alkylene;
y is an integer from 0 to 3;
z is an integer from 0 to 5;
X is —N =, —CH = or —CR 5 =;
R 1 is hydrogen, substituted or non-substituted alkyl, substituted or non-substituted heteroalkyl, substituted or not substituted cycloalkyl, substituted or not substituted heterocycloalkyl, substituted or not substituted aryl, or containing or non-substituted heteroaryl;
R 3 , R 4 and R 5 independently represent —CN, —S (O) n R 6 , —NR 7 R 8 , —C (O) R 9 , —NR 10 —C (O) R 11 , —NR 12 -C (O) -OR 13 , -C (O) NR 14 R 15 , -NR 16 S (O) 2 R 17 , -OR 18 , -S (O) 2 NR 19 , with or without substituents alkyl substituted or non-substituted heteroalkyl, substituted or not substituted cycloalkyl, substituted or not substituted heterocycloalkyl, substituted or not substituted aryl, or substituted or not substituted heteroaryl, where n represents an integer from 0 to 2, wherein if z is greater than 1, two R 3 groups may be joined together to form substituent or non-substituent cycloalkyl, substituent or non-substituent heterocycloalkyl, substituent or non-substituent aryl, or containing substituents or non-substituted heteroaryl; and
R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 independently represent hydrogen containing substituents or not alkyl containing substituents, substituent or non-substituent heteroalkyl, substituent cycloalkyl, substituent or non-substituting heterocycloalkyl gels, substituent or substituent aryl, or substituent or substituent heteroaryl;
or its racemate, diastereomer, tautomer or geometric isomer, or a pharmaceutically acceptable salt thereof.
7. The ROCK inhibitor according to claim 6, where
L 2 represents methylene;
X represents N = or CH =;
R 1 represents hydrogen; or
y and z are 0.
8. The ROCK inhibitor according to claim 6, where
L 2 represents methylene;
X represents N = or CH =;
R 1 represents hydrogen; and
y and z are 0.
9. The ROCK inhibitor according to claim 6, characterized in that said ROCK inhibitor has the structure:
Figure 00000002
Figure 00000003
or
Figure 00000004
.
10. The composition according to claim 1, containing one or more types of mammalian cells.
11. The mixture containing
one or more types of mammalian cells;
ALK5 inhibitor;
MEK inhibitor; and
ROCK inhibitor.
12. The mixture according to claim 11, characterized in that the mammalian cells include non-pluripotent cells.
13. The mixture according to claim 11, further comprising a glycogen synthase 3 kinase inhibitor (GSK3).
14. The mixture of claim 11, further comprising a histone deacetylase inhibitor (HDAC).
15. A method of inducing non-pluripotent mammalian cells to produce induced pluripotent stem cells, comprising:
the introduction of at least one transcription factor selected from the group consisting of: Oct-3/4, Klf4, Sox2 and c-Myc, in non-pluripotent cells; and
bringing non-pluripotent cells into contact with an ALK5 inhibitor, a MEK inhibitor, and a ROCK inhibitor;
under conditions sufficient to induce pluripotent stem cells.
16. The method according to clause 15, wherein the introduction of at least one transcription factor into non-pluripotent cells includes the introduction of a polynucleotide encoding the specified at least one transcription factor into non-pluripotent cells.
17. The method according to clause 15, wherein the introduction of at least one transcription factor into non-pluripotent cells includes contacting the non-pluripotent cells with a polypeptide containing the amino acid sequence of the specified at least one transcription factor polypeptide.
18. The method according to clause 15, further comprising bringing non-pluripotent cells into contact with a GSK3 inhibitor.
19. The method according to clause 15, further comprising bringing non-pluripotent cells into contact with an HDAC inhibitor.
20. The method according to clause 15, wherein the ROCK inhibitor has the structure:
Figure 00000001
Where
L 2 represents substituent or non-substituent C 1 -C 10 alkylene;
y is an integer from 0 to 3;
z is an integer from 0 to 5;
X is —N =, —CH = or —CR 5 =;
R 1 is hydrogen, substituted or non-substituted alkyl, substituted or non-substituted heteroalkyl, substituted or not substituted cycloalkyl, substituted or not substituted heterocycloalkyl, substituted or not substituted aryl, or containing or non-substituted heteroaryl;
R 3 , R 4 and R 5 independently represent —CN, —S (O) n R 6 , —NR 7 R 8 , —C (O) R 9 , —NR 10 —C (O) R 11 , —NR 12 -C (O) -OR 13 , -C (O) NR 14 R 15 , -NR 16 S (O) 2 R 17 , -OR 18 , -S (O) 2 NR 19 , with or without substituents alkyl substituted or non-substituted heteroalkyl, substituted or not substituted cycloalkyl, substituted or not substituted heterocycloalkyl, substituted or not substituted aryl, or substituted or not substituted heteroaryl, where n represents an integer from 0 to 2, wherein if z is greater than 1, two R 3 groups may be joined together to form substituent or non-substituent cycloalkyl, substituent or non-substituent heterocycloalkyl, substituent or non-substituent aryl, or containing substituents or non-substituted heteroaryl; and
R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 independently represent hydrogen containing substituents or not alkyl containing substituents, substituents or substituents heteroalkyl, substituents cycloalkyl, substituents or substituents heterocycloalkyl, substituents or substituents aryl, or substituents or substituents heteroaryl;
or its racemate, diastereomer, tautomer or geometric isomer, or a pharmaceutically acceptable salt thereof.
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US25254809P true 2009-10-16 2009-10-16
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